Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides.

Abstract

Transthyretin amyloidosis (ATTR amyloidosis) is a rare disease that results from the deposition of misfolded transthyretin (TTR) protein from the plasma into tissues as amyloid fibrils, leading to polyneuropathy and cardiomyopathy. IONIS-TTRRx (ISIS 420915) is a 2nd-Generation 2'-O-(2-methoxyethyl) modified "2'-MOE" antisense oligonucleotide (ASO) that targets the TTR RNA transcript and reduces the levels of the TTR transcript through an RNaseH1 mechanism of action, leading to reductions in both mutant and wild-type TTR protein. The activity of IONIS-TTRRx to decrease TTR protein levels was studied in transgenic mice bearing the Ile84Ser human TTR mutant, in cynomolgus monkeys and in healthy human volunteers. Robust (>80%) reductions of plasma TTR protein were obtained in all three species treated with IONIS-TTRRx, which in mice and monkeys was associated with substantial reductions in hepatic TTR RNA levels. These effects were dose-dependent and lasted for weeks post-dosing. In a Phase 1 healthy volunteer study, treatment with IONIS-TTRRx for four weeks was well tolerated without any remarkable safety issues. TTR protein reductions up to 96% in plasma were observed. These nonclinical and clinical results support the ongoing Phase 3 development of IONIS-TTRRx in patients with ATTR amyloidosis.

• Authors: Elizabeth J Ackermann, Shuling Guo, Merrill D Benson, Sheri Booten, Sue Freier, Steven G Hughes, Tae-Won Kim, T Jesse Kwoh, John Matson, Dan Norris, Rosie Yu, Andy Watt, Brett P Monia
• Journal: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis (Amyloid) Vol. 23 Issue 3 Pg. 148-157 (Sep 2016) ISSN: 1744-2818 [Electronic] England
• PMID: 27355239 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)

Chemical References

• Oligonucleotides, Antisense
• Prealbumin
• RNA, Messenger
• Ribonuclease H
• ribonuclease HI

Topics

• Adolescent
• Adult
• Amyloid Neuropathies, Familial (therapy)
• Animals
• Double-Blind Method
• Female
• Gene Expression
• Healthy Volunteers
• Hep G2 Cells
• Hepatocytes (cytology, metabolism)
• Humans
• Liver (metabolism)
• Macaca fascicularis
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Oligonucleotides, Antisense (administration & dosage, pharmacokinetics)
• Prealbumin (antagonists & inhibitors, biosynthesis, genetics)
• Primary Cell Culture
• RNA Cleavage
• RNA, Messenger (antagonists & inhibitors, biosynthesis, genetics)
• Ribonuclease H (metabolism)